Gene therapy restores vision in rd1 mice after removal of a confounding mutation in Gpr179

The rd1 mouse with a mutation in the Pde6b gene was the first strain of mice identified with a retinal degeneration. However, AAV-mediated gene supplementation of rd1 mice only results in structural preservation of photoreceptors, and restoration of the photoreceptor-mediated a-wave, but not in restoration of the bipolar cell-mediated b-wave. Here we show that a mutation in Gpr179 prevents the full restoration of vision in rd1 mice. Backcrossing rd1 with C57BL6 mice reveals the complete lack of b-wave in a subset of mice, consistent with an autosomal recessive Mendelian inheritance pattern. We identify a mutation in the Gpr179 gene, which encodes for a G-protein coupled receptor localized to the dendrites of ON-bipolar cells. Gene replacement in rd1 mice that are devoid of the mutation in Gpr179 successfully restores the function of both photoreceptors and bipolar cells, which is maintained for up to 13 months. Our discovery may explain the failure of previous gene therapy attempts in rd1 mice, and we propose that Grp179 mutation status should be taken into account in future studies involving rd1 mice

Antimicrobial resistance patterns and risk factors associated with salmonella spp. Isolates from poultry farms in the east coast of peninsular malaysia: A cross-sectional study

The burden of antimicrobial use in agricultural settings is one of the greatest challenges facing global health and food security in the modern era. Malaysian poultry operations are a relevant but understudied component of epidemiology of antimicrobial resistance. We aimed to identify the prevalence, resistance patterns, and risk factors associated with Salmonella isolates from poultry farms in three states of East Coast Peninsular Malaysia. Between 8 February 2019 and 23 February 2020, a total of 371 samples (cloacal swabs = 259; faecal = 84; Sewage = 14, Tap water = 14) was collected from poultry operations. Characteristics of the sampled farms and associated risk factors were obtained using semi-structured questionnaires. Presumptive Salmonella spp. isolates were identified based on colony morphology with subsequent biochemical and PCR confirmation. Susceptibility of isolates was tested against a panel of 12 antimicrobials using disk diffusion method. Our findings revealed that the proportion of Salmonella spp.-positive isolates across sample source were as following: cloacal swab (46.3%, 120/259); faecal (59.5%, 50/84); in tap water (14.3%, 2/14); and in sewage sample (35.7%, 5/14). Isolates from faecal (15.5%, 13/84), cloacal (1.2%, 3/259), and sewage (7.1%, 1/14) samples were significantly resistant to at least five classes of antimicrobials. Resistance to Sulfonamides class (52%, 92/177) was predominantly observed followed by tetracycline (39.5%, 70/177) and aminoglycosides (35.6%, 63/177). Multivariate regression analysis identified intensive management system (OR = 1.55, 95% CI = 1.00–2.40) as a leading driver of antimicrobial resistance (AMR) acquisition. A prevalence of resistance to common antimicrobials was recorded for sulfamethoxazole (33.9%), tetracycline (39.5%), and trimethoprim-sulphamethoxazole (37.9%). A close association between different risk factors and the prevalence of AMR of Salmonella strains sug-gests a concern over rising misuse of veterinary antimicrobials that may contribute to the emergence and evolution of multidrug-resistant pathogen isolates. One Health approach is recommended to achieve a positive health outcome for all species

Response rates of standard interferon therapy in chronic HCV patients of Khyber Pakhtunkhwa (KPK)

<p>Abstract</p> <p>Background</p> <p>Interferon based therapy is used to eradicate the Hepatitis C Virus from the bodies of the infected individuals. HCV is highly prevalent in Khyber Pakhtunkhwa (KPK) that is why it is important to determine the response of standard interferon based therapy in Chronic HCV patients of the region.</p> <p>Study design</p> <p>A total of 174 patients were selected for interferon based therapy. The patients were selected from four different regions of KPK. After confirmation of active HCV infection by Real Time PCR, standard interferon with ribavirn was given to patients for 6 months. After completion of therapy, end of treatment virologic response (ETR) was calculated.</p> <p>Results</p> <p>Out of total 174 patients, 130 (74.71%) showed ETR and 44 (25.28%) did not show ETR. In district Bunir, out of 52 patients, 36 (69.23%) showed ETR and 16 (30.79%) did not show ETR. In district Mardan, out of the total 74 patients, 66 (89.18%) were negative for HCV RNA and 8 (10.81%) were resistant to therapy. In Peshawar, out of 22, 16 (60%) were negative and 6 (40%) were positive for HCV RNA at the end of 6 months therapy. In the Federally Administered Tribal Area (FATA), out of 18 only 10 (55.5%) were negative and 8 (44.45%) were positive for active HCV infection.</p> <p>Conclusion</p> <p>It is concluded that the response of antiviral therapy against HCV infection in chronic HCV patients of KPK province is 74.71%. The high response rate may be due to the prevalence of IFN-responsive HCV genotypes (2 and 3) in KPK.</p

Rapid fluvial remobilization of sediments deposited by the 2021 Chamoli disaster, Indian Himalaya

High-magnitude mass flows can have a pervasive geomorphological legacy, yet the short-term response of valley floors to such intense disturbances is poorly known and poses significant observational challenges in unstable landscapes. We combined satellite remote sensing, numerical modeling, and field observations to reconstruct the short-term geomorphological response of river channels directly affected by the 7 February 2021 ice-rock avalanche−debris flow in Chamoli district, Uttarakhand, India. The flow deposited 10.4 ± 1.6 Mm3 of sediment within the first 30 km and in places reset the channel floor to a zero-state condition, requiring complete fluvial re-establishment. In the 12 months post-event, 7.0 ± 1.5 Mm3 (67.2%) of the deposit volume was removed along a 30-km-long domain and the median erosion rate was 2.3 ± 1.1 m a−1. Most sediment was removed by pre-monsoon and monsoon river flows, which conveyed bedload waves traveling at 0.1−0.3 km day−1 and sustained order-of-magnitude increases in suspended sediment concentrations as far as 85 km from the event source. Our findings characterize a high-mountain fluvial cascade with a short relaxation time and high resilience to a high-magnitude geomorphological perturbation. This system response has wider implications, notably for water quality and downstream hydropower projects, which may be disrupted by elevated bedload and suspended sediment transport

Specialist training in Fiji: Why do graduates migrate, and why do they remain? A qualitative study

<p>Abstract</p> <p>Background</p> <p>Specialist training was established in the late 1990s at the Fiji School of Medicine. Losses of graduates to overseas migration and to the local private sector prompted us to explore the reasons for these losses from the Fiji public workforce.</p> <p>Methods</p> <p>Data were collected on the whereabouts and highest educational attainments of the 66 Fiji doctors who had undertaken specialist training to at least the diploma level between 1997 and 2004. Semistructured interviews focusing on career decisions were carried out with 36 of these doctors, who were purposively sampled to include overseas migrants, temporary overseas trainees, local private practitioners and public sector doctors.</p> <p>Results</p> <p>120 doctors undertook specialist training to at least the diploma level between 1997 and 2004; 66 of the graduates were Fiji citizens or permanent residents; 54 originated from other countries in the region. Among Fiji graduates, 42 completed a diploma and 24 had either completed (21) or were enrolled (3) in a master's programme. Thirty-two (48.5%) were working in the public sectors, four (6.0%) were temporarily training overseas, 30.3% had migrated overseas and the remainder were mostly in local private practice. Indo-Fijian ethnicity and non-completion of full specialist training were associated with lower retention in the public sectors, while gender had little impact. Decisions to leave the public sectors were complex, with concerns about political instability and family welfare predominating for overseas migrants, while working conditions not conducive to family life or frustrations with career progression predominated for local private practitioners. Doctors remaining in the public sectors reported many satisfying aspects to their work despite frustrations, though 40% had seriously considered resigning from the public service and 60% were unhappy with their career progression.</p> <p>Conclusion</p> <p>Overall, this study provides some support for the view that local or regional postgraduate training may increase retention of doctors. Attention to career pathways and other sources of frustration, in addition to encouragement to complete training, should increase the likelihood of such programmes' reaching their full potentials.</p

Reconciliation of the carbon budget in the ocean’s twilight zone

Photosynthesis in the surface ocean produces approximately 100 gigatonnes of organic carbon per year, of which 5 to 15 per cent is exported to the deep ocean1, 2. The rate at which the sinking carbon is converted into carbon dioxide by heterotrophic organisms at depth is important in controlling oceanic carbon storage3. It remains uncertain, however, to what extent surface ocean carbon supply meets the demand of water-column biota; the discrepancy between known carbon sources and sinks is as much as two orders of magnitude4, 5, 6, 7, 8. Here we present field measurements, respiration rate estimates and a steady-state model that allow us to balance carbon sources and sinks to within observational uncertainties at the Porcupine Abyssal Plain site in the eastern North Atlantic Ocean. We find that prokaryotes are responsible for 70 to 92 per cent of the estimated remineralization in the twilight zone (depths of 50 to 1,000 metres) despite the fact that much of the organic carbon is exported in the form of large, fast-sinking particles accessible to larger zooplankton. We suggest that this occurs because zooplankton fragment and ingest half of the fast-sinking particles, of which more than 30 per cent may be released as suspended and slowly sinking matter, stimulating the deep-ocean microbial loop. The synergy between microbes and zooplankton in the twilight zone is important to our understanding of the processes controlling the oceanic carbon sink

A Nested Case-Control Study of Intrauterine Exposure to Persistent Organochlorine Pollutants in Relation to Risk of Type 1 Diabetes

BACKGROUND: The incidence of type 1 diabetes in Europe is increasing at a rate of about 3% per year and there is also an increasing incidence throughout the world. Type 1 diabetes is a complex disease caused by multiple genetic and environmental factors. Persistent organochlorine pollutants (POPs) have been suggested as a triggering factor for developing childhood type 1 diabetes. The aim of this case-control study was to assess possible impacts of in utero exposure to POPs on type 1 diabetes. METHODOLOGY/ PRINCIPAL FINDINGS: The study was performed as a case-control study within a biobank in Malmö, a city located in the Southern part of Sweden. The study included 150 cases (children who had their diagnosis mostly before 18 years of age) and 150 controls, matched for gender and day of birth. 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) and the major DDT metabolite 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE) were used as a biomarkers for POP exposure. When comparing the quartile with the highest maternal serum concentrations of PCB-153 with the other quartiles, an odds ratio (OR) of 0.73 (95% confidence interval [CI] 0.42, 1.27) was obtained. Similar results was obtained for p,p'-DDE (OR 0.56, 95% CI 0.29, 1.08). CONCLUSIONS: The hypothesis that in utero exposure to POPs will trigger the risk for developing type 1 diabetes was not supported by the results. The risk estimates did, although not statistically significant, go in the opposite direction. However, it is not reasonable to believe that exposure to POPs should protect against type 1 diabetes

Relevance of large litter bag burial for the study of leaf breakdown in the hyporheic zone

Particulate organic matter is the major source of energy for most low-order streams, but a large part of this litter is buried within bed sediment during floods and thus become poorly available for benthic food webs. The fate of this buried litter is little studied. In most cases, measures of breakdown rates consist of burying a known mass of litter within the stream sediment and following its breakdown over time. We tested this method using large litter bags (15 x 15 cm) and two field experiments. First, we used litter large bags filled with Alnus glutinosa leaves (buried at 20 cm depth with a shovel) in six stations within different land-use contexts and with different sediment grain sizes. Breakdown rates were surprisingly high (0.0011–0.0188 day-1) and neither correlate with most of the physico-chemical characteristics measured in the interstitial habitats nor with the land-use around the stream. In contrast, the rates were negatively correlated with a decrease in oxygen concentrations between surface and buried bags and positively correlated with both the percentage of coarse particles (20–40 mm) in the sediment and benthic macro-invertebrate richness. These results suggest that the vertical exchanges with surface water in the hyporheic zone play a crucial role in litter breakdown. Second, an experimental modification of local sediment (removing fine particles with a shovel to increase vertical exchanges) highlighted the influence of grain size on water and oxygen exchanges, but had no effect on hyporheic breakdown rates. Burying large litter bags within sediments may thus not be a relevant method, especially in clogged conditions, due to changes induced through the burial process in the vertical connectivity between surface and interstitial habitats that modify organic matter processing